Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge

Abstract

Sufficient uptake and whole body distribution of vitamin C (ascorbate) is essential for many biochemical processes, including some that are vital for tumor growth and spread. Uptake of ascorbate into cancer cells is modulated by availability, tumor blood flow, tissue diffusion parameters, and ascorbate transport proteins. Uptake into cells is mediated by two families of transport proteins, namely, the solute carrier gene family 23, consisting of sodium-dependent vitamin C transporters (SVCTs) 1 and 2, and the SLC2 family of glucose transporters (GLUTs). GLUTs transport the oxidized form of the vitamin, dehydroascorbate (DHA), which is present at negligible to low physiological levels. SVCT1 and 2 are capable of accumulating ascorbate against a concentration gradient from micromolar concentrations outside to millimolar levels inside of cells. Investigating the expression and regulation of SVCTs in cancer has only recently started to be included in studies focused on the role of ascorbate in tumor formation, progression, and response to therapy. This review gives an overview of the current, limited knowledge of ascorbate transport across membranes, as well as tissue distribution, gene expression, and the relevance of SVCTs in cancer. As tumor ascorbate accumulation may play a role in the anticancer activity of high dose ascorbate treatment, further research into ascorbate transport in cancer tissue is vital.

Keywords: ascorbate; expression; sodium-dependent vitamin C transporter 1; sodium-dependent vitamin C transporter 2; tumor.

Figure 1

Ascorbate levels in normal tissue are not associated with ascorbate levels in tumors from endometrial and colorectal cancer patients. Tissue samples from patients with endometrial (n = 50) and colorectal cancer (n = 50) were processed, and ascorbate levels (nanomoles per microgram DNA) were measured using HPLC-EC [data from Ref. (17, 18)]. From each patient, samples were obtained from tumor and adjacent normal tissue. There was no association between ascorbate content in tumor vs. normal tissue in individual patients with endometrial or colorectal cancer (Pearson correlation: R² = 0.001, p = 0.81, and R² = 0.022, p = 0.30, respectively). Hence, whole body ascorbate status may not predict tumor ascorbate status.